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Hepatitis C

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according to National Health and Nutrition examination Survey ... Tatoos. Acupuncture. Ear Piercing. These ARE NOT usual causes of HCV! Indications For Tx ... – PowerPoint PPT presentation

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Title: Hepatitis C


1
Hepatitis C
2
HCV OverviewHepatitis C Why Study?
  • Most common chronic blood-borne infection in the
    USA
  • 3.9 million Americans infected with HCV (1.8 of
    pop.) according to National Health and Nutrition
    examination Survey (NHANES III)
  • 2.7 million have chronic HCV (HCV RNA detected in
    serum)
  • Worldwide, 170 million infected with HCV (3 of
    pop.)
  • Annual incidence of new cases is decreasing from
    230,000 per year in 1980s to 32,000 per year in
    1990s
  • Chronic HCV-associated liver disease is on rise

3
  • Part of Flaviviridae family of viruses
  • Associated with both human and animal disease
  • 3 genera pestiviruses (cattle, pigs),
    flaviviruses (dengue, yellow fever),
    hepaciviruses (HCV)
  • In hepacivirus family
  • 6 major clades
  • gt100 different subtypes
  • Countless quasispecies mult. seen in each
    infected individual

4
HCV Structure
  • RNA virus
  • Single-stranded
  • Positive-sense
  • 9400 nucleotide
  • Virion
  • Enveloped
  • Icosahedral capsid
  • 40-60 nm in diameter

5
HCV Genome
  • 1 hypervariable region
  • E1, E2 envelope proteins
  • Allows for evasion of host immunologic response
  • 9400 nucleotide, single ORF
  • Codes for a viral polyprotein about 3000 a.a. in
    length
  • 3 highly conserved areas
  • 5 UTR initiating translation
  • Core codes for capsid protein monomer
  • 3 UTR essential for RNA synthesis packaging

6
HCV Natural History
  • Study of Infection, Replication and Release
    Difficult
  • Lack of reliable culture system
  • Does not integrate into host genome
  • Low number of circulating virions

7
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8
Binding and Entry
  • Unknown at this time
  • Guesses
  • E2 binds to CD81 on liver
  • Envelope protein binds to CD81 large
    extracellular loop
  • E2 binds to LDLR
  • Envelope coated with LDL during secretion?

9
Translation
  • Activation of Translation
  • 5 NCR shown to have IRES activity
  • Cap-independent initiation
  • Ribosomal 40s subunits, eIF3 bind to IRES
    regions?

10
Processing of Polyprotein
  • Cleaved by signal peptidase in ER Core, E1, E2,
    p7, NS2
  • NS2/3 autoprotease cleaves at NS2-Ns3 junction
  • Cysteine peptidase
  • No other known function
  • NS3 serine protease domain cleaves rest of
    polypeptide
  • NS4A is cofactor for NS3 cleavage

11
Replication, Assembly And Release
  • Replication
  • Poorly understood
  • NS5b polymerase, NS3 helicase domain, host
    factors all involved
  • Assembly and Release
  • Capsid protein interacts with 5 NCR
  • Homotypic capsid protein interaction
  • E1 and E2 on ER membrane
  • Nucleocapsid precursors bud into ER to aquire
    envelope
  • Pass through host secretory pathway, released
  • All this questionable

12
Evasion of Immune Response
  • HCV is RNA virus mutates quickly
  • E1, E2 in hypervariable region changes often
  • NS5A inhibits PKR
  • PKR is effector of host antiviral defense
    pathway represses translation by phosphorylating
    eIF2
  • NS5A has other activities as well less understood

13
Pathology of HCV
  • Acute Hepatitis C
  • Generally benign
  • No jaundice (80)
  • Usually asymptomatic
  • Can be severe, but liver failure rare
  • Only real threat of acute Hepatitis C is its
    ability to reach chronic stages undetected and
    untreated.

14
Pathology of HCV
  • Chronic Hepatitis C
  • 70 of patients become chronic
  • Possible results
  • Cirrhosis
  • End-stage liver disease
  • Hepatocellular carcinoma

15
Some pictures of liver disease
Incidence of HCC 17x greater in HCV-infected than
in HCV-negative patients.
16
Transmission
  • Direct blood or fluid exposure
  • Sexual Activity
  • Perinatal Transmission

17
Transmission
  • Other things thought to be associated with HCV
  • Tatoos
  • Acupuncture
  • Ear Piercing

These ARE NOT usual causes of HCV!
18
Indications For Tx
  • Increased ALT activity
  • Liver biopsy fibrosis
  • Detectible serum HCV RNA

19
Treatment
  • Vaccine
  • Difficult
  • High mutation rate
  • Attempts
  • DNA Vaccine codes for capsid protein

20
Treatment
  • Antivirals
  • Interferon alpha mainstay
  • Monotherapy or in conjunction with Ribavirin
  • Liver Transplant

21
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22
A Very Incomplete Bibliography
  • Braunwald et al Harrisons Principles of
    Internal Medicine, 15th ed. pp 1725-1751
  • Fischers Virology, Vol 1. Unk. Edition
  • Zuckerman and Thomas Viral Hepatitis Scientific
    Basis and Clinical Management. pp 229-326
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